Method of preparing derivatives of morpholine and thiamorpholine



Patented 8, 1945 METHOD OF PREPARING DERIVATIVES F MORPHOLINE ANDTHIAMORPHOLINE Gaetano F. DAlelio and James J. Pyle, Pi-ttsfield, Mass.,assignors to General Electric Company, a corporation of New York NoDrawing. Application June 2, 1943, Serial No. 489,384

9 Claims.

This invention relates to the preparation of derivatives of morpholineand thiamorpholine which may be represented graphically by the followinggeneral formula:

where Y is a member of the class consisting of oxygen and sulfur, and Ris a member of the class consisting of hydrogen and monovalenthydrocarbon radicals. Illustrative examples of monovalent hydrocarbonradicals that R in the formula may represent are: aliphatic (e. g.,methyl, ethyl, propyl, isopropyl, ally], :butyl, sea-butyl, isobutyl,butenyl, amyl, isoamyl, hexyl, etc.) including cycloalihatic (e. g.,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, etc.)aryl (e. g., phenyl, diphenyl or xenyl, naphthyl, etc.)aliphatic-substituted aryl (e. g., tolyl, xylyl, ethylphenyl,propylphenyl, isopropylphenyl, a1- lylphenyl, etc.) and aryl-substitutedaliphatic (e. g., benzyl, phenylethyl, phenylpropyl, cinnamyl, etc.).Preferably R represents hydrogen.

Although compounds such, for instance, asbeta-N-morpholino-propionitrile and gamma-N- morpholino-butyronitrileare known, the compounds resulting from the methods of the presentinvention are distinguished from such known compounds by the fact thatthe cyano group is attached directly to the nitrogen atom of themorpholine ring.

The N-cyano compounds embraced by Formula I may be used aschemo-therapeutic agents and, also, as intermediates in the preparationof derivatives thereof such, for instance, as carbamy1, thiocarbamyl,imido ether, amidine, acyl,

.trile type and other thermoplastic resins. Alde-.

hyde reactablederivatives of the compounds embraced by Formula I, e. g,,N-carbamyl and N- thiocarbamyl morpholines and thiamorpholines, may becondensed with, for instance, aldehydes,

, including polymeric aldehydes and aldehyde-ad- I ing arts.

pounds produced therefrom that have unsatis factory plasticity or flowcharacteristics, including resins of the. acrylonitrile an methacryloni-In practicing our invention we prepare compounds of thekind embraced byFormula I by effecting reaction between (1) a morpholine or athiamorpholine that is unsubstituted in the N position and whichcorresponds to the general formula car-o a, II NH o R2- on, n where Yand R. have the same meanings as given above with reference to FormulaI, and (2) a cyanogen halide (cyanogen chloride, cyanogen bromide,cyanogen fluoride, cyanogen iodide), the said reaction preferably beingeffected in the presence of a hydrohalide acceptor. Illustrativeexamples or morpholines and thiamorpholines that may be used, dependingupon the particular end product desired, are listed below. It will benoted that this list includes examples of morpholines andthiamorpholines having various hydrocarbon substituents, includingalkyl, alkenyl,

cycloalkyl, aryl, alkaryl and aralkyl substituent groupings, attached toone or more carbon atoms of the morpholine nucleus.

Morpholine Thiamorpholi'ne 2 -methylmorpholine 3.-ethylmorpholines-propylmorpholine 3,5-dimethylmorpholine 2,6-dimethylmorpho1ine2-methyl 5-isopropyl morpholine Z-methyl 5-isobutyl thiamorpholineE-propylthiamorpholine 3-allyl G-butyl thiamorpholine3,3-dimethylmorpholine Z-ethyl 5-butenyl thiamorpholine 2-amyl 3-hexylG-butenyl thiamorpholine Z-isopropyl 3-methyl B-butyl thiamorpholine2,3,5 -trimethylmorpholine 2,3,5,6-tetraethylmorpholine 3-methyl5-phenyl morpholine 3-allyl 5-cycloherqrl B-phenyl morpholine Z-xenyl6,6-ditoiyl thiamorpholine 2,2,3,3,5,5,6,6-octaetbylmorpholinez-cinnamyl 3-methyl 5 --cycloheptyl 6,- phenyl morpholine3-cyclohexylmorpholine 2-ethylphenyl 3-benzyl 6-tolyl morpholine3-phenethyl 5-propyl 6,6-dimethyl thiamorpholine 2-allyl 5-isoamylG-naphthyl thiamorpholine 2-allylphenyl 5-isoamyl 6-phenyl morpholine2-allyl 5,5-dicyclohexyl 6-tolyl morpholine S-phenylpropyl 6-cinamy1morpholine 2,2-diphenyl 5-t0lyl G-allylphenyl thiamorpholineZ-phenylmorpholine 2,2-dibenzyl 3-allylphenyl S-propylphenyl morpholine2-methyl 3-ethyl 5-propy1 B-butyl morpholine 2,2-dimethyl 3,3-diethyl5,5-dipropyl, 6,6-dibutyl thlamorpholine 2,2-diethyl 3,3-diphenyl5,5-dicyclohexyl 6,6-dipropyl morpholine 3-naphthylmorpho1ine5-xenylthiamorpholine Illustrative examples of hydrohalide acceptorsthat may be used are the inorganic bases, e. g., the alkali-metalhydroxides (sodium hydroxide, potassium hydroxide, etc.), calciumhydroxide, barium hydroxide, strontium hydroxide, etc., the carbonatesof such bases, and the organic bases, for instance trimethyl amine,tributyl amine, dimethyl aniline, pyridine, quinoline, a morpholine or a'thiamorpholine (numerous examples of which have been given above),etc., quaternary ammonium bases (9. g., tetramethyl ammonium hydroxide,etc.) and the like. We prefer to use an excess of the morpholine orthiamorpholine reactant as the hydrohalide acceptor.

For economic reasons and because of their availability we prefer toemploy cyanogen bromide or cyanogen chloride as the cyanogen halidereactant.

The reaction between the morpholine (or thiamorpholine) and the cyanogenhalide may be carried out in any suitable manner, but preferably isefiected in the presence of a suitable solvent or mixture of solvents.Although various solvents or solvent mixtures may be employed, we preferto use petroleum ether or diethyl ether. However,

- other solvents including water may be employed instead of the organicsolvents just mentioned. The reaction may be carried out under a varietyof temperature and pressure conditions, for instance at normal or atelevated temperatures and at atmospheric,subatmospheric or super-atmosepheric pressures.

The above reaction may be represented by the following equation:

CRa-CR:

" hydrohalido acceptor NCX CBr-C 2 cards,

'/N--CN salt of hydrohalide acceptor CRr-GR:

In the above equation X represents a halogen and R and Y have the samemeanings as given hereinbefore with reference to Formula I.

In order that thoseskilled in the art better may understand how thepresent invention may be carried into effect, the following examples aregiven by way of illustration and not by way of limitation. All parts areby weight.

Example 1 This example illustrates the preparation N- cyanomorpholine,the formula for which is CHr-CH:

1v 0 N-CN CH:C 2

Parts- Mol ratio Morpholine 1 87.0 2 Cyanogen bromide 52. 5 l Ethyletlier 1,500.0

'lhe exc ss of morpholine over that required for reaction withthecyanogen bromide functions as a hydrohalide acceptor- The cyanogenbromide dissolved in one-half the above-stated amount of ethyl ether(diethyl ether) was added dropwise to a cold solution of the morpholinedissolved in the remainder (750 parts) of the ether. The solution forstirred continuously at room temperature (Zoe-C.) for 4 to 5 hoursduring which time a white precipitate of morpholine hydrobromide formed.The precipitate was filtered ofi and washed with ether. (The morpholinemay be recovered for reuse by regenerating with an alkali, e. g., sodiumhydroxide.) The filtrate and washings were concentrated under reducedpressure, yielding 55.2 parts N-cyanomorpholine. This corresponds to 92per cent of the theoretical yield. The N- cyanomorpholine boiled atl17-1l9 C. at 15 mm. pressure.

Instead of using an excess (one mol in excess of equimolecularproportions) of morpholine as a hydrohalide acceptor, other hydrophalldeacceptors such as mentioned hereinbefore may be employed.

. Example 2 N-cyanothiamorpholine, the formula for which Is cur-c112 .vI s N-CN CHrcz is prepared in essentially the same manner as describedunder Example 1 with reference to the production of N-cyanomorpholinewith the ex ception that 103 parts thiamorpholine are used instead of8'7 parts morpholine.

, that 115 parts 2,6-dimethy1 morpholine are used in place of 87 partsmorpholine.

It will be readily understood by those skilled in the art from theforegoing description of the preparation of N-cyanomorpholine,N-cyanothiamorpholine and 2,6-dimethyl N-cyanomorpholine that, when itis desired to produce a morpholine pounds corresponding to the generalformula 2-methy1 4-cyano 5-isobutyl thiamorpholine 2-amyl B-hexyl4-cyano 2-'-allyl. 4-cyano r asvaeas having a cyano groupattacheddirectly to the at least oneqethyl, propyl, butyl, 'butenyl or otheralkyl or alkenyl group, or other aliphatic -or other hydrocarbonsubstituent (e. g., an aromatic hy ocarbon radicaliattacheddirectly toat least on -carbon atom of the morpholine nucleus,then the startinreactants and amounts thereof are chosen so as 1:0 yield the desiredproduct in accordance with methods such as given above my way orillustration.- v

xMore specific'examples of chemical compounds embraced by Formula Ithatmay be produced by praeticingnour invention are chemical comcu -ch,

responding to the general formula:

in I ca er;

Y r 501v I where Y is. a member of the class consisting of oxygen andsulfur,and R represents a monovalent aliphatic hydrooarbon radical, e.g., an

alkyl or alkenyl radical.lther specific exampies are as follows:

3-ethy1 a-cya'no morpholine (4 -cyano -ethy1 morpholinei l 3-propy14-cyan0 morpholine (4.-cyano 5-propylmorpholine) 3,5-dimethy1 4-cyanomorpholine 2-methyl 4-cyano S-isopropyl morpholine (3-isopropyl 4-cyanoG-methyl morpholine) 3-propyl 4-cyano' thiamorpholine (4-cyano 5-propylthiamorpholine) 3-allyl 4-cyano 6-butyl thiamorpholine3,3-dimetbyl 4-cya'no morpholine (4-cyano 5,5-

dimethyl morpholine) i l p 2-ethyl 4-cyano S-butenyl thiamorpholine.

G-butenyl thiamorpholine i 2-isopropyl 3-methyl d-cyano 6-butylthiamorpholine i g x 2,3,5-trimethyl 4-cyano morpholine2,3,5,6-tetraethyl 4-cyano morpholine 3-methyl 4-cyano 5-phenylmorpholine 3-allyl 4'-cyano 5-cyclohexyl d-phenyl morpho- Hn i2--xeny1,4-cyano 6,6-ditoly1 thiamorpholine u a2,2,3,3,5,5,6,6-octaethyl 4-cyano morpholine z-cinnamyl .3-methyl4-cyano 5-cyclohepty1 -6 'phenyl morpholine 3-cyclohexyl 4-cyano mor-',pholine .(4-cyano 5.-cyclohexyl morpholine) Z-ethyIphenyI 3-benzyl4-cyano 6-tolylmorphov l i w i 4-cyano 5-xenyl thiam '2,2-diethylftah-aiphenyl v a 2,2-dibenz'yl 3-allylphenyl 4-cyano 5-propyl nitrogenatom 01' the morpholine nucleus and phenyl morpholine 2 -methyl ii-ethylpholine 2,2-dimethy 3 dibutyl thiamorp hexyl '6,6dipro'p'yl morpholi3-nabhthy1A-cyano mor holine thyl morpholine) v rpholine,thiamorpholine) l Specific method features or theu nvention include themethod o: preparinghcompositions ens-om j Hr-Q 1 t a where Y has thesame meaning as xgi-ven above and (2) a cyanogen halide, specificallycyanogen chloride or bromide, under the conditions hereinbefore morefully described. Our invention. also provides a method oipreparingN-cyanomorpholine which comprises effecting reactionibetween morpholineand a cyanogen halide, ,specifi ca lly cyanogen. chloride orbromideninvthe'rpresence of a hydrohalide acceptor andyisolating;Nscyanomorpholine from the reaction-mass; A'morespecifiamethod feature"omourrninvention:ris the method of preparingN-cyanomorpholine;whichcomprises: efiecting" reaction between :morpholine and a cyanogenhalide, more particularly cyanogen chloride or bromide,while the saidreactants are dissolved in a so1vent,-the morpholine being in excess ofequimoiecular proportions, and separating N-cyanomorpholine' e. g., bydistillation under reduced pressure, from the reaction amass.

What we claim as newaand desire wto .asecure by Letters PatentoftheqUnited States.:--;is'-

1. The method of preparing an M-cyanQzco mu- 7 pound corresponding tothe general formula CBFCR:

N-CN cat on;

' where Y is a membertor-rthe"class consisting of z-allyphenyl 4 -cyano'S-isoamyl timb fll orgi tupholinet v 3-phenylpropyl 4-c'yano 6-cinnamylmorpholine 2,2-diphenyl"=i4-cyano 5-tol'yl fi-allylphenyl thiamorpholine'2-phenyl4-cyano morpholine (4-cyano G-phenyl morpholine) pounds of (1)and- (2) while admixed with the amount of the compound of (1) in molarex- F css of the aforesaid equimolecular proportions, 'the said molarexcess of the compound of (1) reacting with the hydrogen halide producedduring the reaction between the equimolecular proportions of thecompounds oi (1) and (2) to form a salt of the compound of (1) andisolating the N,-cyano compound from the reaction mass.

2. A method as in claim 1 wherein the cyanogen halide is cyanogenchloride.

3. A method as in claim 1 wherein the cyanotween equimolecularproportions of the compounds of (1) and (2) while admixed with the 6.The method or preparing N-cyanomorpholine which comprises mixingtogether morpholine and cyanogen chloride in proportions correspondingto at least about two mols oi" the forme per mol of the latter, allowingto react at no al temperature equimolecular proportions of themorpholine and cyanogen chloride while adm ed. with the amount of themorpholine in molar excess of the aforesaid equimolecular proportions,the said molar excess of morpholine reacting with the hydrogen chlorideproduced during the reaction between the equimolecular proportions ofmorpholine and fcyanogen chloride to form a amount of the compound of(1) in molar excess of the aforesaid equimolecular proportions, the saidmolar excess of the compound ofv (1) reacting with the hydrogen chlorideproduced during the reaction-between the equimolecular proportions ofthe compounds of (1) and (2) to form a salt of the compound of (1), andisolating the N-cyano compound from the reaction mass.

5. The method of preparing an N-cyano compound corresponding to thegeneral formula CHI-CH2 CHz-CH:

where Y is a member of the class consisting of oxygen and sulfur, saidmethod comprising mixing together (1) a compound corresponding to thegeneral formula cH'i-cH, Y

\C H2Cfi2 where Y'has the same meaning as given above and (2) cyanogenbromide in proportions corresponding to at least about two mols of theformer per mol of the latter, efiecting reaction between equimolecularproportions of the compounds of (1) and (2) while admixedwith the amountof the compound of (1) in molar excess of the aforesaid equimolecularproportions, the said molar excess of the compound of (l) reacting withthe hydrogen bromide produced during the reaction between theequimolecular proportions of the compounds of (l) and (2) to form a saltof the compound of (1) and isolating the N-cyano compound from thereaction mass.

morpholine salt, and isolating N-cyanomorpholine from the reaction mass.

7. The method of preparing N-cyanomorpholine which comprises mixingtogether morpholine and cyanogen bromide in proportions corresponding toat least about two mols of the former per mol of the latter, allowing toreact at normal temperature equimolecular proportions of the morpholineand cyanogen bromide while admixed with the amount of the morpholine in'molar excess of the aforesaid equimolecular proportions, the said molarexcess of morpholine reacting with the hydrogen bromide produced duringthe reaction between the equimolecular proportions of morpholine andcyanogen bromide to form a morpholine salt, and isolating N-cyanomorpholine from the reaction mass.

8. The method of preparing N-cyanomorpholine which comprises mixingtogether a solution of morpholine and a solution of cyanogen bromide,the said reactants being present in the mixture in proportionscorresponding to at least two mols morpholine per molcyanogen bromide,effecting reaction at 20 to 30 C. between equimolecular proportions ofthe dissolved morpholine andcyanogen bromide while admixed with theamount of dissolved morpholine in molar excess of the aforesaidequimolecular proportions, the said molar excess of morpholine reactingwith the hydrogen bromide produced during the reaction between theequimolecular proportions of morpholine and cyanogen bromide to form amorpholine salt, and recovering N-cyanomorpholine from the reactionmass.

9. The method of preparing N-cyanomorpholine which. comprises slowlyadding a solution of cyanogen bromide dissolved in diethyl ether to asolution of morpholine dissolved in diethyl A ether, the said reactantsbeing present in the resulting mixture in proportions corresponding toat least two mols morpholine per mol cyanogen bromide, stirring themixture at 20 to 30 C. for

4 to 5 hours thereby to eflect reaction between equimolecularproportions of the dissolved morpholine and cyanogen bromide whileadmixed with the amount of dissolved morpholine in molar excess of theaforesaid equimolecular proportions, the said molar excess of morpholinereacting with the hydrogen bromide produced during the reaction betweenthe equimolecular proportions of morpholine and cyanogen bromide to forma morpholine salt, filtering oi the morpholine salt, washing theseparated morpholine salt with diethyl ether, and recoveringN-cyanomorpholine from the filtrate and washings. GAETANO F. D'ALELIO.

JAMES J. PYLE.

